Cohort Profile: The Shanghai Maternal-Child Pairs Cohort (MCPC)

Abstract

The Shanghai Maternal-Child Pairs Cohort (MCPC) was the first cohort study conducted following the full implementation of China's two-child policy. It aims to investigate the role of psychological factors and environmental exposure omics in the development and progression of common childhood disorders. Between April 2016 and October 2018, we enrolled 6714 eligible pregnant women in Shanghai. They were followed up closely throughout pregnancy, with 5507 mothers remaining in the cohort at delivery after excluding stillbirths, miscarriages, and loss to follow-up. The children were subsequently followed up at birth, 42 days, 4, 6, 9, 12, and 24 months and 3–5 years of age, with an average follow-up rate exceeding 70%. The study dataset contains information including demographics, environmental exposures, maternal stress, social support, behavioural lifestyles, biophysical measurements, neurocognitive development, language assessment, body surface characteristics and the shape and structure of the spine. Additionally, over 520 000 biological samples were collected from mother-child pairs, including fingernail, hair, blood, urine, placenta, meconium and breast milk from mothers, as well as fingertip blood, buccal mucosa, feces and urine from children. The Shanghai MCPC encourages collaboration and welcomes specific queries regarding research proposals and data analysis. For further information, please get in touch with its principal investigators at [[email protected]] or [[email protected]]. Numerous studies have increasingly demonstrated that the aetiology of chronic diseases, including autism, hyperactivity, asthma, diabetes, obesity and cardiovascular diseases, can be traced back to early life, underscoring the importance of health promotion in fetuses and infants. As a result, interest has grown among the public regarding the impact of maternal environmental and psychological factors on pregnancy and child development. With the recent rapid socioeconomic transition and development in recent years, China's landscape is undergoing unprecedented changes. Shanghai, located on the Yangtze River Delta in eastern China, has rapidly grown into an international metropolis as one of China’s earliest ports for global trade and commerce in China. However, the expeditious economic growth in Shanghai has brought with it a drawback, that is daily environmental contamination stemming from large amounts of various traditional and emerging pollutants. In particular, pregnant women in Shanghai, as a susceptible population, may be exposed to high levels of emerging pollutants, such as per- and polyfluoroalkyl substances (PFAS) and organophosphate pesticides,1,2 raising concerns for their health and the wellbeing of their unborn offspring. Furthermore, although novel alternatives to emerging pollutants have received widespread attention, there is still a lack of systematic research regarding their associated physical and mental health risks. In addition to exposure to environmental pollution, the highly competitive and rigorous lifestyles of people living in Shanghai have led to changes in their social and psychological behaviours,3,4 including high stress, poor sleep and irregular schedules, which in turn cause greater psychological stress during pregnancy. This stress can potentially affect parenting behaviour and the growth environment for children. Within the unique context of Shanghai, this city provides researchers with an appropriate population to investigate the associations between adverse exposures during early life and health, a crucial aspect of the Developmental Origins of Health and Disease (DOHaD) theory. Shanghai Maternal-Child Pairs Cohort (MCPC) was supported by the Shanghai Municipal Education Commission-Gaofeng Public Health Grant Support, the National Key Research and Development Program of China and the National Natural Science Foundation of China. Its recruitment began in April 2016, coinciding with the abolition of the one-child policy and the full implementation of the two-child policy in China.5 Given the many costs, pressures and challenges brought by raising more than one child, the Shanghai MCPC was the first prospective birth cohort study conducted in the wake of this comprehensive family planning policy change. This comprehensive study investigates the influence of psychological factors and exposome, as well as genetic and behavioural factors, on maternal and child health throughout prenatal and early life. It aims to identify the key risk factors for childhood conditions, including birth size, congenital anomalies, growth retardation, allergies and neurobehavioural disorders. In addition, the Shanghai MCPC enables assessments of the interactions of these factors, key developmental stages and underlying biological pathways that might exist, through multi-omics analyses including genomics, metabolomics and microbiome, contributing to improving the physical and mental health of mothers and children in China. The Shanghai MCPC study recruited registered pregnant women during 12–16 gestational weeks in Fudan University Affiliated Pudong Hospital or Songjiang Maternity & Child Health Hospital between April 2016 and October 2018. Eligible women had to be at least 20 years of age, with a minimum 1-year residency in Shanghai, without chronic diseases before pregnancy, intending to undergo prenatal care and delivery at either of these two hospitals, able to complete Chinese questionnaires without difficulty, and willing to remain in Shanghai for more than 3 years post-delivery. Husbands of eligible women were also invited to participate in the study. Written informed consent was obtained from all study participants, with the option to withdraw at any time. In total, 8021 eligible pregnant women were approached and 6714 provided consent (response rate 83.71%). The contrasting characteristics between responders and non-responders are shown in Supplementary Table S1 (available as Supplementary data at IJE online). However, 5507 remained at delivery after exclusion due to stillbirth, miscarriage and the loss to follow-up. Supplementary Table S2 (available as Supplementary data at IJE online) shows the comparison of baseline information between the pregnant women lost to follow-up and those who were successfully followed up at delivery. Supplementary Tables S1 and S2 (available as Supplementary data at IJE online) indicate that pregnant women with lower educational levels or lower socioeconomic status tended to refuse to participate in the cohort or follow-up. However, there was no significant difference in the baseline information of those who completed follow-up at various time points during pregnancy (shown in Supplementary Table S3, available as Supplementary data at IJE online), demonstrating the stability of pregnant women in the Shanghai MCPC. In the Shanghai MCPC study, complete parental demographic information was collected at 12–16 gestational weeks. Maternal clinical measurements were recorded throughout the prenatal care and hospitalization process at 12–16, 24–28 and 32–36 gestational weeks and delivery. Medical records were used to obtain birth outcomes and newborn information. The mother-child pairs received a routine and compulsory postpartum clinical health examination 42 days after birth. Follow-up visits were arranged for the children at ages 4, 6, 9, 12 and 24 months, and were incorporated into their kindergarten physical examinations from the age of 3 years. Each visit included a thorough health examination. Special emphasis was placed on studying child growth trajectories, developmental disorders, neurocognitive development and parenting behaviour. A visual representation of the cohort participant composition during the study period is presented in Figure 1. Flow chart of the Shanghai Maternal-Child Pairs Cohort Study participants. LESPW, Life Events Scale for Pregnant Women; SAS, Self-rating Anxiety Scale; CES-D, Center for Epidemiological Studies Depression Scale; RSA, Resilience Scale for Adults; FFQ, Food Frequency Questionnaire; PSQI, Pittsburgh Sleep Quality Index; IPAQ, International Physical Activity Questionnaire; ASQ-3, Ages and Stages Questionnaire, third edition; ISPQ, Infant Sociality Performance Questionnaire; SDQ, Strengths and Difficulties Questionnaire; WPPSI-IV, Wechsler Preschool and Primary Scale of Intelligence, fourth edition; M-CHAT, Modified Checklist for Autism in Toddlers; CPLS, Chinese Preschool language Scale Figures 2 and 3 delineate the detailed information gathered for the parents and children participating in the cohort study. In Figure 2, the parents’ baseline questionnaire comprised a thorough enquiry about demographics, employment details, dwelling environment, lifestyle and medical history. Furthermore, detailed data regarding the lifestyle and the potential exposure to hazards for pregnant women were collected at the first visit and during the 32–36 gestational weeks. The exposure included pesticides, insecticides, paint, heavy metals, air pollution, noise, high temperature and X-rays, existing in their employment or dwelling environment. Physical activity was evaluated through the Chinese version of the International Physical Activity Questionnaire (IPAQ),6 and sleep quality via the Pittsburgh Sleep Quality Index (PSQI).7 Additional questionnaires were also administered at the same time, aimed to evaluate their psychological stress and resilience, including the Self-rating Anxiety Scale (SAS),8 the Center for Epidemiological Studies Depression Scale (CES-D),9 the Life Events Scale for Pregnant Women (LESPW)10 and the Resilience Scale for Adults (RSA).11 However, the dietary intake of the pregnant women was assessed using the Food Frequency Questionnaire (FFQ) only during the 32–36 gestational weeks. The Edinburgh Postnatal Depression Scale (EPDS) was employed as a screening tool for postpartum depression at 42 days after birth.12 Clinical data were recorded during pregnancy, encompassing anthropometric measurements, prenatal screening outcomes, ultrasound findings, prescribed medication and mode of delivery. Data and specimen collection for parents participating in the Shanghai Maternal-Child Pairs Cohort. PSQI, Pittsburgh Sleep Quality Index; IPAQ, International Physical Activity Questionnaire; FFQ, Food Frequency Questionnaire; LESPW, Life Events Scale for Pregnant Women; SAS, Self-rating Anxiety Scale; CES-D, Center for Epidemiological Studies Depression Scale; RSA, Resilience Scale for Adults; EPDS, Edinburgh Postnatal Depression Scale Data, specimen and special phenotypes collection for children in the Shanghai Maternal-Child Pairs Cohort. FFQ, Food Frequency Questionnaire; CPCIS, Chinese Parent-Child Interaction Scale; ACE-IQ, Adverse Childhood Experiences-International Questionnaire; CTQ-SF, Childhood Trauma Questionnaire-Short Form; ASQ-3, Ages and Stages Questionnaire, third edition; ISPQ, Infant Sociality Performance Questionnaire; SDQ, Strengths and Difficulties Questionnaire; WPPSI-IV, Wechsler Preschool and Primary Scale of Intelligence, fourth edition; M-CHAT, Modified Checklist for Autism in Toddlers; CPLS, Chinese Preschool language Scale Figure 3 shows children’s physical measurements and gestational age at birth, obtained from the medical records. During early childhood, trained paediatricians conducted routine physical measurements and clinical assessments at each follow-up visit, adhering to standard operating procedures. Besides this, detailed information on lifestyle, dwelling environment and medical history was also collected via interviewing the parents. Parent-child interactions were thoroughly evaluated by employing the Chinese parent-child interaction scale (CPCIS).13 Moreover, the Childhood Trauma Questionnaire-Short Form (CTQ-SF)14 and Adverse Childhood Experiences-International Questionnaire (ACE-IQ)15 were used to determine the extent of childhood maltreatment and adverse experiences, respectively. An extensive face-to-face assessment of neurodevelopment was conducted during follow-up, including the Chinese version of the Ages and Stages Questionnaire, third edition (ASQ-3), at 42 days of age, 6 months of age and after 1 year of age,16 and the Infant Sociality Performance Questionnaire (ISPQ) was incorporated at 6 and 12 months of age to assess social responsiveness.17 After 2 years of age, children's emotional and behavioural issues were evaluated using the Strengths and Difficulties Questionnaire (SDQ).18 Additionally, language development was tested via the Chinese Preschool Language Scale (CPLS) for children between 3 and 5 years of age. Furthermore, intellectual development was assessed using the Wechsler Preschool and Primary Scale of Intelligence, fourth edition (WPPSI-IV).19 The risk of autism spectrum disorder (ASD) was evaluated using the Modified Checklist for Autism in Toddlers (M-CHAT),20 and children who screened positive were referred to the specialist clinic. During pregnancy, various bio-samples such as fingernails, hair, venous blood and urine were collected from mothers. Upon delivery, cord blood, placenta and meconium samples were obtained as well. After birth, breast milk samples were collected from mothers, and fingertip blood, buccal mucosa, feces and urine were obtained from children at most of the follow-up points. Furthermore, skilled technicians recorded body surface characteristics (facial features and skin patterns) and the shape and structure of the spine for children 3–5 years of age in kindergarten, according to standard operating procedures. Over 520 000 biological samples have been collected from mother-child pairs to date. Table 1 presents an overview of the main characteristics of the study population. Notably, the average ages of the enrolled mothers and fathers were 28.33 and 31.60 years, respectively, and the corresponding average pre-pregnancy body mass indexes (BMIs) were 21.20 kg/m2 and 23.71 kg/m2. The data showed that over 40% of the parents had received a college-level education or higher. Additionally, most of the couples were employed, with an annual household income ranging from 100 000 to 300 000 RMB. The study revealed a low prevalence of tobacco smoking exposure in mothers during pregnancy, but an appreciably higher prevalence in fathers. Of the enrolled mothers, 55.03% were unipara, and the caesarean delivery rate was found to be 50.43% after excluding pregnant women who were lost to follow-up. For children, 50.87% were male and the average gestational age at birth was 39.06 weeks. Furthermore, the mean birthweight and length were 3321.60 g and 49.93 cm, respectively. The study also noted the overall incidences of low birthweight, macrosomia and preterm birth, which were observed to be 3.00%, 6.44% and 4.57%, respectively. Basic characteristics of participants in the Shanghai Maternal-Child Pairs cohort BMI, body mass index; RMB, renminbi; SD, standard deviation. Using data from the Shanghai MCPC study, our research has employed a lot of exposure-outcome associations during pregnancy and early life, including air pollution, heavy metals, antibiotics and emerging chemicals such as PFAS, organophosphorus flame retardants and plasticizers. The study confirmed that maternal exposure to environmental pollutants had adverse effects on pregnancy outcomes and the offspring's neurocognitive development and physical growth. Specifically, exposure to particulate matter with particles with a diameter of 2.5 μm or less (PM2.5) was found to be significantly related to increased maternal blood pressure, anxiety [odds ratio (OR) 1.23, 95% confidence interval (CI) 1.04-1.46], and depression (OR 1.27, 95% CI 1.04-1.55) during pregnancy, and also associated with the disrupted fetal growth and neurocognitive development impairment for children.21–25 Furthermore, intrauterine penicillin and lactational polybrominated diphenyl ether exposure reduced infants' early growth,26,27 and cumulative prenatal exposure to low-dose penicillin increased the risk of delivering a large-for-gestational-age (LGA) baby (OR 1.03, 95% CI 1.00-1.05).28 Notably, prenatal exposure to PFAS was linked to adverse effects on childhood neurocognitive development (OR 1.23, 95% CI 1.03-1.46), and the effects of PFAS mixtures were higher than those of single congeners.29 Additionally, maternal strontium and lithium exposures were found to contribute to gestational weight gains,30 and prenatal vanadium exposure exhibited gender-specific effects on fetal growth.31 Interestingly, offspring catch-up growth risk increased with the combination of increasing pre-pregnancy BMI and maternal abnormal blood glucose level [risk ratio (RR) 5.24, 95% CI 1.78-15.43].32 Moreover, we combined exposome with metabolomics and epigenetic analysis to investigate potential underlying molecular mechanisms. Our findings indicated that decreased maternal fT4 levels could mediate the effect of PM2.5 exposure and its constituents on disrupted fetal growth.23 Additionally, the disruptions of grow-related cytokines such as interleukin-6 and growth differentiation factor-15 were shown to contribute to the effect of prenatal vanadium exposure on fetal growth, and the second trimester appeared to be the sensitive window.31 Furthermore, the small extracellular vesicle-derived microRNAs in the placenta, especially microRNA-320a-3p, may contribute to an increased risk of infant neurocognitive developmental delay due to PM2.5 exposure.24 More research is currently underway to investigate the effects and biological mechanisms of prenatal and early life exposures to the potential hazards. Our study also produced abundant results regarding the health risks of maternal emotional stress and lifestyles. The findings suggested that maintaining good lifestyles and emotional wellbeing in pregnant women can positively impact on pregnancy health and children's neurocognitive development and physical growth. Our research indicated that physical activity can significantly improve sleep quality in pregnant women. Moderate physical activity levels at both 12–16 gestational weeks (β -0.42, 95% CI -0.68–0.16) and 32–36 gestational weeks (β -0.32, 95% CI -0.63-0.01) were significantly associated with lower PSQI scores.33 Moreover, high physical activity levels were found to be more effective in reducing PSQI scores at 32–36 weeks (β -0.87, 95% CI -1.57-0.18).33 The study also revealed that adverse sleeping habits are linked to gestational diabetes mellitus and offspring overweight/obesity within 24 months.34 Maternal prenatal depression and anxiety rates were respectively 10.3% and 11.1% in the Shanghai MCPC study. Our research uncovered that serum oxytocin levels in the second trimester functioned as a modification factor between early pregnancy stress and prenatal anxiety and depression.35 Additionally, resilience played a crucial role in mitigating the harmful effects of stress in early pregnancy.36 Maternal prenatal emotional symptoms were observed to be positively associated with the risk for LGA delivery (OR 1.42, 95% CI 1.04-1.94) 37 and children's neurocognitive development at 24 months of age—an association that was mediated by microbial richness indices and Lactobacillus.38 Furthermore, parenting practices a role in the development of children. high (OR 95% CI and exposure (OR 95% CI to were found to be linked to lower risks of developmental was found to be associated with children's sleep at 2 years of age. with children without children who in were more to sleep issues (OR 95% CI and (OR 95% CI in the Shanghai MCPC study are on the at studies on the between the environment, maternal parenting and children’s development, to specific for the health of The Shanghai MCPC study had the cohort used a to biological and follow-up visits that to The and combined with biological of risk factors, and our cohort an of the neurocognitive development and through language development assessment and special encompassing children's body surface characteristics (facial features and skin patterns) and and of the spine. the cohort recruited a higher of participants with higher who had a greater to It also that might more psychological stress, be more and more parenting our cohort a transition in birth and environment and might an for policy assessment Furthermore, our study provided unique on prenatal and early life exposures and their potential health effects on the Chinese population. the the Shanghai MCPC study also had common The participants in the cohort were to Shanghai to follow-up, which might be of the population in the pregnant women had their first visits after 12 gestational which it to women in the early stages of pregnancy, from the effects of exposure in early pregnancy. the cohort biological samples from or venous blood from children, from associations between factors and children's these be and to information about the Shanghai MCPC study, such as questionnaires and comprehensive research are available on the Shanghai MCPC study at For on our research and please get in touch with the [[email protected]] and [[email protected]]. The Shanghai MCPC study was by the Fudan University and to the by the and on Moreover, it is conducted in with the of in regarding research get of the Supplementary data are available at IJE and were for the study and and the of the and the the analysis and of and were for pregnant women. of the to the of the and of the This is supported by the National Key Research and Development Program of China the National Natural Science Foundation of China and the Shanghai Municipal Education Commission-Gaofeng Public Health Grant our to and for their on the Shanghai MCPC. all the participating and the Shanghai MCPC for their significant to this It is to that the presented in this study is the of the and the of the Shanghai Municipal Education and Health Moreover, we that we such as in our

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